The range and severity of CF disease is extremely heterogeneous. Our evaluation of a large number of well defined patients with "typical" and "atypical" CF disease and those suspected of having CF are elucidating the relative influence on the disease phenotype of genetic factors including the different CFTR gene mutations and other modulatory genetic factors. Our overall goal is to establish a comprehensive understanding of the spectrum of CF disease associated with mutations and/or variants in the CFTR gene. As well, some variability in CF disease expression between patients with the same genotype (and in specific organs) will be due to the effects of "Modifier" genetic variants on a patient's genome. The specific aims of this application are to: . define CF phenotypes by identifying CFTR gene mutations in well defined patient cohorts with: a conventional diagnosis of CF, "atypical" CF and those suspected of having CF. . define the natural history of CF disease in patients with CFTR gene mutations who are diagnosed by conventional diagnostic criteria or have "atypical" CF phenotype including males with infertility and patients with idiopathic pancreatitis. . determine the frequency of CFTR gene mutations in cohorts with disease phenotypes resembling CF including asthma, chronic lung disease, and neonates with high immunoreactive trypsinogen and normal sweat test. . evaluate obligate heterozygotes with different CFTR gene mutations for evidence of CF phenotypes. . determine, in the above mentioned patient cohorts, the relative influence in the CF phenotype the different CFTR gene mutations and modifier genes. Taken together, we will help to clarify the diagnosis of CF disease and ultimately, our findings will lea to significant advances in diagnosis and therapy.